The study of antitumor immunity and the elimination of factors that cause its deterioration are important problems in modern medicine. Malignant neoplasms occupy one of the leading places among the causes of death and disability in the developed countries. Normally, the balance of the number of dividing and dying cells is naturally regulated. If cell reproduction becomes uncontrolled, then malignant tumors arise. The mechanism of control of this process by the immune system depends on several factors that suppress or stimulate the process of excessive division.
General Description
Under immunity is commonly understood as a set of protective mechanisms of a living organism from the negative effects of foreign agents. Most often, these processes are associated with infectious (bacterial, viral, fungal, protozoal) diseases. However, there are other ways of protection, one of which is antitumor immunity.
In the activities of any livingthe body has moments when it needs rapid cell division (trauma, inflammation, and others). With the development of a certain immune response, the number of cells sensitive to the effects of an antigen (a molecule associated with an antibody) increases several thousand times. In the normal course of the process, after the completion of this reaction, the accelerated cell division stops.
For a malignant tumor is characterized by a violation of this mechanism. Reproduction of cells continues constantly and has an independent character. Gradually, normal tissues are replaced in the affected organ and the tumor grows into the surrounding areas. Moving along the bloodstream, tumor cells continue to divide in other localization, which leads to the appearance of metastases. This defect in continuous division is inherited by all descendants of tumor cells. Their membranes are modified in such a way that the human body perceives objects as foreign.
On the other hand, there is a way in the body that can stop this process - antitumor immunity. In immunology, the occurrence of tumors is evidence that a violation of the natural defense mechanism has occurred.
Discovery history
Even in the 18th century, it was noticed that some patients who had infectious diseases disappeared malignant tumors. At the end of the 19th century, the American oncologist surgeon William Coley identified the relationship between infection with hemolytic streptococcus Streptococcus pyogenes and the reduction (and in some cases even complete disappearance) of tumors.malignant nature. He developed a cancer vaccine based on these bacteria to treat patients with sarcoma. At that time, the mechanisms of antitumor immunity in immunology were not yet known, so his work was subjected to strong criticism, and subsequently was forgotten for almost 100 years.
In the middle of the 20th century, it was discovered that the introduction of liposaccharide macromolecules, which make up the membranes of microbial cells, can lead to the death of tumors. However, in the 70s. 20th century scientists have found that this process is not caused by liposaccharide itself, but by a protein factor (tumor necrosis factor, or TNF), produced by the following types of cells of the immune system when in contact with microbes:
- activated macrophages;
- neutrophils;
- T-lymphocytes;
- mast cells;
- astrocytes;
- NK cells (natural killer cells).
Relationship between immunity and tumor formation
The following facts testify in favor of the connection between the state of immunity and the development of malignant tumors:
- increased prevalence of such neoplasms in immunocompromised patients, as well as in the elderly (associated with a decrease in the body's defenses);
- detection in patients of specific antibodies and T-cells sensitive to tumor antigens;
- possibility of formation of antitumor immunity and immunoproliferative diseases (with artificial administration of antibodies and immune suppression, respectively).
The protective function of immunity consists not only in the destruction of foreign agents (viruses, fungi and bacteria), but also mutant cells from which tumors are formed. They are characterized by antigenic specificity, which depends on the cause of the neoplasm:
- viruses (papillomas, leukemia and others);
- chemical carcinogens (methylcholanthrene, benzopyrene, aflatoxins and others);
- endocrine disorders (metabolic immunosuppression);
- physical environmental factors (all types of radiation).
Natural antitumor immunity has very little effect on an already formed malignant neoplasm. This is attributed to the following factors:
- rapid growth of the tumor, ahead of the activation of immune forces;
- isolation by tumor cells of antigens that bind the corresponding receptors on the surface of killer lymphocytes;
- suppression of cellular immunity by neoplasm.
Operation principle
The mechanism of antitumor immunity in medical science is still little understood. Despite the fact that its protective function has been identified, antibodies can reflect tumor antigens without causing destruction of malignant cells. In some cases, immunotherapy even backfires, causing the growth to grow.
According to modern concepts, activated macrophages and killer cells play a key role in this process. A feature of antitumor immunity is that itcharacterized by a complex mechanism of interaction between the host organism and the neoplasm. There are 4 main groups of factors:
- Antiblastoma - humoral and cellular (T-lymphocytes, TNF, macrophages, NK- and K-cells, specific antibodies, interferons, interleukins), suppressing the development of a tumor and destroying its cells.
- Immunoresistance of a neoplasm, or its ability to resist antitumor immunity.
- Problastoma: immunosuppressive (substances-suppressors produced by macrophages and lymphocytes; hormone-like compounds, interleukin-10, circulating immune complexes, proteins of the TGFβ group, consisting of antigens, antibodies and complement components); enhance immunity (TNF produced by macrophages; gamma-interferon, interleukins 2 and 6, endothelial growth factor; immunodeficiency states).
Effector mechanisms
The main function of the effector mechanisms of antitumor immunity is to block and destroy pathogens. There are 2 groups of receptors that selectively bind to specific antigens. Based on this, 2 types of effector mechanisms are also distinguished:
- Humoral, functioning due to soluble (humoral) factors - antibodies that bind and remove the antigen.
- Cellular (antibody-independent), realized with the participation of cells of the immune system, the most important of which are T-lymphocytes, macrophages, NK-cells. They directly destroy foreign, infected and tumor cells.
If a pathologically altered cell avoided death under the influence of effector mechanisms, then a period of equilibrium between its division and the overwhelming influence of immunity may begin. With the progression of the malignant process, the tumor tissue gets out of control of immune mechanisms.
The most important role in the suppression of cell division is played by 2 types of lymphocytes that trigger the process of necrosis - T-lymphocytes and NK-cells that recognize stress molecules that the neoplasm releases. T-lymphocytes are formed over a longer time, and their precursors recognize tumor antigens. Th1-lymphocytes trigger the mechanism of inflammation, which leads to the activation of macrophages. The secretion products of the latter contribute to the disruption of local blood supply to tissues, which also leads to the death of tumor tissues.
The participation of T-lymphocytes is manifested in the impregnation of a malignant neoplasm with lymphoid cells, which destroy its cells by dissolution, or cytolysis. The activation of lymphocytes occurs under the action of cytokines - protein information molecules, with which they penetrate into the tumor together.
Gamma-interferon is also of great importance among the internal factors inherent in the immune system of the human body. Its functions are as follows:
- Suppression of tumor cell division.
- Activation of the process of their programmed death.
- Stimulating the production of cytokines that attract T-lymphocytes to the neoplasm.
- Activation of macrophages and development of T-helpers,needed to strengthen antitumor immunity.
- Suppression of the formation of new blood vessels, which impairs the nutrition of the tumor and contributes to the faster death of its cells.
Antineoplastic immunity: reasons for its low effectiveness
The growth of malignant neoplasms and their resistance to immunity are explained by the following reasons:
- weak ability to induce an immune response in tumor antigens;
- survival (natural selection) of immune resistant tumor cells;
- constant modification of antigens;
- presence of a capsule in the tumor;
- secretion of tumor antigens in soluble form, resulting in suppression of the immune response;
- Location of the neoplasm in places where the occurrence of the antigen does not lead to an inflammatory immune response (the so-called "privileged" localization - bone marrow, nervous, endocrine and reproductive systems, thymus);
- loss of some components of the effector system as a result of genetic or acquired (secondary) immunodeficiency conditions;
- production of problastoma factors by tumor cells that suppress immunity and promote tumor growth;
- in newborns - immaturity of effector systems, resulting in non-recognition of tumor cells.
These mechanisms of inefficiency of antitumor immunity lead to the fact that the neoplasm becomes less immunogenic and is not perceived by the bodyas a foreign element. As a result, the protective reaction is reduced. Immune mechanisms cannot lead to rejection of an already formed malignant tumor.
Features
Features of antitumor immunity include:
- The main role in the immune response is played by T-lymphocytes, macrophages and NK cells that destroy tumor tissue. The value of humoral immunity is much less.
- Cancer antigens are recognized either directly by macrophages and dendritic cells responsible for innate and adaptive immunity, or through Th1 helpers.
- Interaction between the organism and the tumor occurs in three directions: natural and acquired resistance to malignant neoplasms, immunosuppression by the tumor. The combination of these factors constitutes antitumor immunity.
- Malignant cells in the process of natural selection acquire defense mechanisms against innate immunity. Their new phenotype is being formed, the neoplasm is evolving.
Tumor-associated antigens are divided into 2 groups - the first type (characteristic of many types of neoplasms, are of viral origin) and the second, very specific and found in all patients with this type of tumor.
One of the common features of antiviral and antitumor immunity is that it is both specific, that is, directed against certain types of pathogens, and non-specific (destroys allforeign to the body). Nonspecific factors are mononuclear and NK cells activated under the influence of interleukin 2 and interferons, as well as lymphokine-activated killer cells and cytokines.
Immunodiagnostics
In recent years, immunodiagnosis of malignant neoplasms has been used in medicine. It is based on the detection of the following protein compounds in the blood:
- antigens associated with tumors;
- antibodies;
- lymphocytes susceptible to tumor antigens.
- PSA (prostate).
- P-53 (bladder).
- SCC (lungs, esophagus, rectum).
- CA-19-9 (pancreas).
- CA-125 (ovaries).
- CA-15-3 (mammary gland).
However, antibodies to a certain antigen in the blood of patients with cancer are determined infrequently (in 10% of cases). Immunoglobulins to tumor-associated antigens are detected more often - in 50% of patients. The medical science community is currently searching for other antigens to help diagnose cancer.
Immunoprophylaxis and treatment
To increase antitumor immunity, immunomodulators are used that indirectly activate cells of the immune system:
- Interleukins 1 and 2. These protein compoundsbelong to the group of pro-inflammatory cytokines (information molecules) and are biologically active substances produced by leukocytes. Interleukins are the main participants in the formation of the immune response during the introduction of pathogens in microbiology. Antitumor immunity is activated due to the active division of lymphocytes (T-killers, NK-cells, T-helpers, T-suppressors and antibody producers). Interleukin 2 also activates the production of tumor necrosis factor.
- Drugs from the group of interferons. They stimulate an immune response by presenting antigens to T-lymphocytes that have been taken up by macrophages and dendritic cells. T-helpers secrete protein information molecules that activate the work of other cells of the immune system. The result is an increase in antitumor immunity. Certain types of interferons (interferon gamma) can directly affect macrophages and killers.
- Adjuvants. They are administered together with the main immunobiological medicines and serve to enhance the response of the body's defenses. Most often they are used for he althy people when vaccinated. One of the features of antitumor immunity in microbiology concerning this type of substances is that they can concentrate antigens on their surface. This provides a longer lasting effect. For targeted delivery of antigens to the organs of the lymphatic system, liposomes are used - vesicles with lipid biolayers. The most common substances in this group are complete and incomplete Freund's adjuvant,aluminum hydroxide, whooping cough deposited on aluminum alum; Polyoxidonium.
- Elements of bacterial cells (immunostimulators Prodigiosan, Likopid, Romurtide and others).
Experiments conducted on animals show that when tumor antigens are injected, immunological memory is formed. As a result, the transplanted malignant tumor is then rejected. In recent years, active developments have been carried out in medicine, which will make it possible to create an antitumor immune memory through vaccination. So far, one type of vaccination has been created in this direction - to increase immunity to human papillomaviruses, which induce the occurrence of cervical cancer in women ("Gardasil" and "Cervarix" of foreign production).
Types of tumors
Immunotherapy is effective against the following types of tumors:
- melanoma arising from melanocytes - pigment cells;
- non-Hodgkin's lymphomas derived from lymphocytes;
- cancer of the kidneys, rectum, ovaries;
- hairy cell leukemia (damage to B-lymphocytes, white blood cells);
- glioma (brain tumor);
- soft tissue sarcoma, the origin of which is associated with epithelial cells and connective tissue.
